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Ketogenic Diets

In aging and many disease states, the energy
production capacity of the body’s cells is diminished.
The mitochondria are the structures within the cell
responsible for generating energy from oxygen and
nutrients. If their number is reduced or their function
is impaired, free radicals are produced and damaging toxins
accumulate in the cells. These toxins further damage the
mitochondria and impair other aspects of cellular function.
Many of the most common health problems, such as obesity,
diabetes, and many problems associated with aging, arise
from problems in cellular energy production. As one group of
researchers has put this, "[a]ging is associated with an overall
loss of function at the level of the whole organism that has
origins in cellular deterioration. Most cellular components,
including mitochondria, require continuous recycling
and regeneration throughout the lifespan."1 Another has
observed, "[m]itochondrial biogenesis [the creation of new
mitochondria] is a key physiological process that is required
for normal growth and development and for maintenance
of ongoing cellular energy requirements during aging."2
These observations link two key aspects of mitochondrial
health, preventing and removing damaged mitochondria
(mitophagy) and creating new mitochondria (mitogenesis).

Although the importance of the mitochondria as a
central point of health has been accepted for decades, over
the last few years the understanding of the mechanisms
involved has changed significantly. Twenty or ten years ago,
antioxidants and the free radical theory of aging largely
dominated thinking. Today, the importance of mitochondrial
biology linking basic aspects of aging and the pathogenesis
of age-related diseases remains strong, yet the emphasis has
changed. The focus has moved to mitochondrial biogenesis
and turnover, energy sensing, apoptosis, senescence, and
calcium dynamics.3

What Promotes Mitochondrial Biogenesis?
The body maintains a complex network of sensors and
signaling functions to maintain stability despite a constantly
changing environment and numerous challenges. Of special
note is the concept of hormesis, meaning a state in which
mild stress leads to compensation that improves the ability
of the body to respond in the future to similar challenges. It
turns out that many of the approaches that are associated
with longevity and healthy aging promote hormesis. In terms of mitochondria biogenesis, these include caloric restriction,
certain nutrient restrictions or shortages, caloric restriction
mimetics, and exercise.

Many of the mechanisms that activate mitochondrial
biogenesis in the face of hormesis have been elucidated.
Keeping in mind that there always must be a balance between
the elimination of worn-out and defective mitochondria and
the generation of new ones, the activators of both actions can
overlap. For instance, low energy levels (caloric restriction)
and increased reactive oxygen species/free radicals can
promote the activity of special cellular control points. These
include activating metabolic sensors such as AMP kinase/
AMPK (adenosine monophosphate kinase) and the protein
known as SIRT1 (sirtuin 1, i.e., silent mating type information
regulation 2 homolog 1). Activated AMPK is an indicator that
cellular energy is low and serves as a trigger to increase
energy production. It inhibits insulin/IGF-1/mTOR signaling,
all of which are anabolic and can lead not just to tissue
production, such as muscle growth, but also to fat storage.
Along with SIRT1, AMPK activates the biogenesis of new
mitochondria to enable the cell to generate more energy. At
the same time, activated AMPK and SIRT1 increase the activity
of a tumor suppressor that induces mitophagy. The balance
of the dual activations replaces defective mitochondria with
newly formed functionally competent mitochondria.

A key to health and healthy aging is to regulate the
catabolic processes via controlled amounts and
types of stressors such that worn out mitochondria
are removed without overshooting the mark and reducing
overall cellular and tissue functionality. The most successful
way to maintain this balance is to follow the body’s own
natural metabolic signals rather than to attempt to override
the body’s checkpoints. AMPK and SIRT1 ultimately are
energy/nutrient sensors or control points. Hence rather than
attempting to manipulate these directly, it likely is safer and
ultimately more effective to address the factors in the cell
that these sensors sense. The recent attention in the issue of
aging to the role of NAD+ (the oxidized form of nicotinamide
adenine dinucleotide) is a good example of this principle.
Directions coming from the nucleus of the cell that help
to regulate the normal production of NAD+ and the ratio
between distinct pools found in the cytoplasm and in the
mitochondria decline with age. The changes in the NAD+
from the nucleus lead to a disruption on the mitochondrial
side. In terms of energy production, it is a bit like losing a link
or two in the timing chain on your car engine with a resultant
reduction in engine efficiency. To date, attempts to increase
NAD+ in cells via supplementation with precursors have
not proven particularly successful. Major benefits have been
demonstrated in animal models only in the already seriously
metabolically impaired or the relatively old. Recent research
on oral supplementation has led to at least one extremely
difficult article which, at least in this author’s opinion, delivers
more smoke than heat.4,5 There is, however, an argument to
the effect that supplementing together both nicotinamide
riboside (a NAD+ precursor) and a sirtuin activator, such as
pterostilbene, may prove to be more successful.

It turns out that there are key points in normal cellular
energy generation processes that strongly influence the
NAD+ pools available for the cell to draw upon and the rate at
which NAD+ can be replaced in these pools. Aging has been
shown to promote the decline of nuclear and mitochondrial
NAD+ levels and to increase the risk of cancer along with
components of the metabolic syndrome. It is significant
that the risks of these conditions can be reduced in tandem.
Three places to start are 1) the pyruvate dehydrogenase
complex, 2) the tricarboxylic acid cycle (TCA cycle) also
known as the Krebs Cycle, and 3) the malate shuttle. A fourth
junction is Complex I of the electron transport system, again,
in the mitochondria.6 Manipulation of steps (1) and (2)
already is being used in cancer treatment.7 Readily available
dietary supplements can influence all four of these metabolic
bottlenecks.

Supplements for Promoting Mitochondrial Biogenesis
Medicine has started to pay a great deal of attention to
effecting mitochondrial biogenesis through not just drugs,
but also dietary supplements. Those interested should
go online and look up "Mitochondrial Biogenesis:
Pharmacological Approaches" in Current Pharmaceutical
Design, 2014, Vol. 20, No. 35. Quite a few options are
mentioned, including well known compounds, such as
R-lipoic acid (including with L-carnitine), quercetin and
resveratrol, along with still obscure supplements, including
various triterpenoids and the Indian herb Bacopa monnieri.

Pomegranate, French White Oak and Walnuts
The pomegranate, with its distinctive scarlet rind (pericarp)
and vibrantly colored seed cases (arils), is one of the oldest
cultivated fruits in the world. This exotic fruit features
prominently in religious texts and mythological tales and has
been revered through the ages for its medicinal properties.
An image of a pomegranate even can be found on the shield
of the British Royal College of Medicine. Numerous studies
have demonstrated the benefits of the fruit for cardiovascular
health with other benefits suggested in areas ranging from
arthritis to stability of cell replication to bone health. Now a
study in Nature Medicine (July 2016) has uncovered perhaps
the most important benefit of all, the ability of pomegranate
compounds (ellagitannins) transformed by gut bacteria to
protect the mitochondria of the muscles and perhaps other
tissues against the ravages of aging. The mitochondria are
the energy generators of the cells and the weakening of
this energy generating function in an increasing percentage
of mitochondria as we age is a primary source of physical
decline over the years. Urolithin A, a byproduct of gut
bacterial action on pomegranate compounds, allows the
body to recycle defective mitochondria and thereby slow or
even reverse for a time some of the major aspects of aging.
The lifespan in a nematode model of aging was increased by
more than 45 percent. Older mice in a rodent model of aging
exhibited 42 percent better exercise endurance. Younger
mice also realized several significant benefits.8

Beginning almost three decades ago, there were
numerous speculations in the research world regarding the
so-called "French Paradox" in which the French consumed
quite large amounts of saturated fat in the form of butter and cheese, yet consistently experienced much lower
rates of cardiovascular disease than did Americans. Not
only that, the French, especially in the southwest of the
country, typically led longer lives even in the areas noted for
consuming large amounts of goose fat and pate de foie gras,
which is to say, not just the Mediterranean diet based on
olive oil, etc. One hypothesis put forth very early on was that
it was the French consumption of red wine that protected
them. It was thought that red wine components, including
anthocyanidins, proanthocyanidins and resveratrol, are the
protective compounds. Not considered until recently is that
French red wines traditionally have been aged in casks made
from white oak (Quercus robur). White oak contains roburin
A, a dimeric ellagitannin related chemically to punicalagin.
Human data show relatively good absorption and conversion
of roburins into substances including urolithin A and ellagic
acid—as compared with ellagitannins in general, which
evidence only poor absorption. Hence, the benefits of good
red wine traditionally produced and good cognac (also aged
in oak barrels) involve urolithin A. Notably, the benefits of
roburins, most likely derived from the conversion to urolithin
A, go beyond mitophagy to include ribosomes, referring to cell
components that translate DNA instructions into specific
cellular proteins.9,10,11,12

Other sources of ellagitannins have been shown to lead
to the production of urolithin A by bacteria in the human
gut. Not surprisingly, sources of ellagitannins are foods
long associated with good health longevity, including not
just pomegranate and oak-aged red wine, but also walnuts
(and a smattering of other nuts), strawberries, raspberries,
blackberries, cloudberries and even black tea in small
amounts.

Exercise and Pyrroloquinoline Quinone (PQQ)
Peroxisome proliferator-activated receptor gamma coactivator
(PGC-1á) is the master regulator of mitochondrial
biogenesis.13 Exercise is perhaps the most significant
activator of PGC-1á that most individuals can access.
Exercise, furthermore promotes mitochondrial biogenesis
through a number of other pathways, especially endurance
and interval training.14

There are non-exercise options. You can’t take PGC-1á
orally because it is a large protein molecule which does not
survive digestion. PQQ is a small molecule that is available
when ingested and that increases circulating PGC-1á. PQQ
supplementation leads to more mitochondria and more
functional mitochondria.15

Fasting, Ketogenic Diets and Fasting-Mimicking Supplements
As already discussed, fasting promotes mitochondrial
biogenesis by AMPK activation.16 AMPK senses the energy
status of the cell and responds both to acute shortages,
such as that induced by exercise, and to chronic shortages,
such as from fasting. Probably due to an overall reduction
in metabolic rate, chronic caloric restriction (as opposed to
intermittent fasting) contributes to the health of mitochondria
rather than biogenesis.17 The robustness of AMPK response
decreases with age.18

Ketogenic diets (very low carbohydrate diets) also
promote increases in mitochondria.19 Few individuals are
willing or able to follow ketogenic diets chronically just as
few individuals are willing to undergo routine fasts. Fasting-mimicking
supplements offer an alternative approach. The
dietary supplement (-)–hydroxycitric acid (HCA) is the best
researched of these compounds. (Keep in mind that there
is a vast difference in the efficacy of commercially available
forms.20) Researchers have proposed that HCA used properly
can activate mitochondrial uncoupling proteins and related
effects.21

Furthermore, according to a study published in the journal
Free Radical Research in 2014, HCA improves antioxidant status
and mitochondrial function plus reduces inflammation in fat
cells.22 Inflammation is linked to the metabolic syndrome at
the cellular level by way of damage to the antioxidant enzyme
system (e.g., superoxide dismutase, glutathione peroxidase,
glutathione reductase) and mitochondria. This damage, in
turn, propagates further production of pro-inflammatory
mediators (e.g., TNF-á, MCP-1, IFN-ã, IL-10, IL-6, IL-1â).
HCA protected fat cells from ER stress by improving the
antioxidant status to reduce oxidative stress (i.e., reduce
ROS) and improve the function of the mitochondria to
short circuit an ER stress—inflammation loop in these cells.
Reducing TNF-á is important in that doing so removes a
major impediment to mitochondrial biogenesis.23

Other Supplements to Promote Mitochondrial Biogenesis

Scholarly reviews looking at natural compounds such as
those that are found in anti-aging diets suggest yet other
supplements to promote mitobiogenesis. For instance,
it turns out that hydroxytyrosol, the most potent and
abundant antioxidant polyphenol in olives and virgin olive
oil, is a potent activator of AMPK and an effective nutrient
for stimulating mitochondrial biogenesis and function via
what is known as the PGC-1á pathway.24 Another herb with anti-aging effect, this time by activating the malate shuttle
mechanism mentioned above, is rock lotus (Shi Lian Hua).
This herb has been described in detail in this magazine in
the article, "Uncovering the Longevity Secrets of the ROCK LOTUS."25

Conclusion
It is possible to improve the functional capacity of the
mitochondria through dietary practices, exercise and
supplements. Indeed, a number of compounds have been
identified by researchers as mitochondrial nutrients. These
compounds work together to increase the efficiency of energy
production, to reduce the generation of free radicals, and so
forth and so on. Likewise, these nutrients have been shown
to improve the age-associated decline of memory, improve
mitochondrial structure and function, inhibit the ageassociated
increase of oxidative damage, elevate the levels
of antioxidants, and restore the activity of key enzymes.
Perhaps best of all, the body can be encouraged both to
remove damaged mitochondria (mitophagy) and to create
new ones, which is to say, mitochondrial biogenesis.

Dallas Clouatre's, PhD, article, is "Caloric Restriction, Ketogenic Diet Or A Third Way?" Clouatre states, "His primary focus of this and related articles has been the concepts of metabolic fitness and metabolic flexibility. Human physiology and metabolism can adapt to a quite wide range of circumstances and can be "tweaked," likewise, with a broad number of approaches. Enhancing healthspan, even if perhaps not absolute lifespan, can be achieved through caloric restriction, fasting and dietary interventions involving properly balanced and selected foods combined with nutrients / dietary supplements. Some of these approaches are more easily sustainable under modern conditions and habits than are others."

Elson Haas, MD, "Food Reactions—The Sensitive Seven," is in reference to Wheat, Cow's milk, Sugar, Eggs, Corn, Soy, and Peanuts. There are many causes of indigestion including too much food, not chewing food thoroughly, and too much liquid while eating. Haas discusses toxins we are exposed to, their impact and the value of detox for us.

Gene Bruno, MS, MHS and Arthur Presser, PharmD present, "The Principles Of Homeopathy." A discussion on the history of homeopathy, how it is formulated and the benefits of use. If you have questions on homeopathy this is a great read on a subject that may appear complex but a natural medicine of value.

Ann Louise Gittleman, PhD, CNS, continues her Smart Fats Series with "Vitamin, Mineral and Amino Acid Deficiencies." The focus is on low thyroid along with all the other reasons behind a metabolic slowdown and the benefits of smart fats as coconut oil, GLA (gamma linolenic acid), CLA (conjugated linoleic acid), omega-7 and pastured butter in correcting problems with metabolism.

Gloria Gilbère, CDP, DAHom, PhD, presents "WAIT...Don't Toss that Pickle Juice!" You'll find dozens of uses for pickle juice. You can make more cucumber pickles, pickle soup, meat marinade, and more suggestions that you haven't thought of—limitless uses and you won't "toss that pickle juice" after reading this article.

Charles K. Bens, PhD, "The Early Detection of Chronic Disease," current blood tests are very inadequate and usually detect chronic disease five to ten years after it has already begun. Good examples are kidney disease, liver disease, heart disease, breast cancer, Alzheimer's, Parkinson's Disease and diabetes. Bens also includes a chart on the five stages of cell deterioration.

Shawn Messonnier, DVM, this month the second and final in the series on, "Rickettsial Diseases." A discussion that includes, fish oils, flaxseed oils Proanthocyanidins and antioxidants, along with other natural treatments and conventional treatments.

Over the last decade, two related types of eating patterns—caloric restriction / fasting diets and ketogenic diets—have begun to attract ever greater attention among university researchers. In this magazine, the first is discussed in "Caloric Restriction, Fasting and Nicotinamide Riboside" (TotalHealth, February 2015).1 The second is examined in "Supplements Target Ketogenesis and Metabolic Flexibility for Sports and Health" (TotalHealth, June 2016).2 Neither of these approaches to influencing aging and health is new, of course. R. H. Weindruch and R. L. Walford already by 1979 had begun publishing major findings on caloric restriction and they were hardly the first to pursue the topic in a serious manner.3,4 As for ketogenic diets, many will remember Robert C. Atkins, Dr. Atkins' Diet Revolution (Bantam, 1972), which was immensely popular for years. Its predecessor was developed in the 1920s for the quite different purpose of treating pediatric epilepsy and was widely used until the introduction of effective anticonvulsant drugs. Outside of epilepsy, until recently the medical world strongly resisted even studying ketogenic diets. A discussion of the use of high-fat/low carbohydrate diets in the early 20th Century for diabetes can be found in my book, Anti-fat Nutrients.5

Taming the CR/Fasting Interventions
Caloric restriction (CR) / fasting and ketogenic dietary
interventions exhibit both overlaps and differences. One major
overlap arises from the fact that caloric restriction, just as does
the ketogenic diet, encourages ketogenesis. Both diets, in their
more pure forms, are quite hard to follow. Caloric restriction
generally involves a 20 to 40 percent reduction in energy intake.
Even at this level, caloric restriction can lead to undesirable
consequences, such as general malnutrition, muscle weakness
and wasting, a failure to adapt to environmental challenges,
neurological deficits, dizziness, irritability, lethargy, and
depression.6

Ketogenic diets have different adverse effects, several of
which are linked to a tendency to avoid almost all fruits and
vegetables, hence losing adequate access to most phytonutrients
and even to many of the canonical vitamins and minerals, such
as vitamin C and potassium. Adverse consequences can include
unwanted weight loss, constipation, kidney stones, calcium
deficiency and other vitamin and mineral deficiencies. At 20 to
50 grams of carbohydrates per day (80 to 200 calories), a medical-style ketogenic diet is difficult to follow. A common failing on ketogenic diets is eating too much protein and too little fat. This defeats at least one of the major goals of ketogenic dieting, which is to reduce insulin-like growth factor 1 (IGF-1).7

Fasting and reduced caloric intake are practices in many
of the world's medical systems, whether for healing or for
preserving health. As but one example, consuming most
food only during a restricted time window, in practice
an eight–ten hour window, and avoiding all solid food
after approximately 4 or 5 p.m. is an ancient Buddhist
recommendation for health. For most individuals, versions
of caloric restriction and/or fasting are far easier to follow
over the long term than is any version of the ketogenic diet.
Furthermore, there are quite a few flexible eating plans
that have been developed to achieve at least some of the
benefits of classic calorie restriction and fasting without
requiring that the adherent become an ascetic.

Approaches to Caloric Restriction and Fasting

Below are some of the defined approaches that have been
worked out by various researchers and writers. For readers
interested in a much more elaborate discussion of these
and related options, an excellent overview can be found in
"Running on Empty: Fasting Diets Are Increasingly Popular,
But Do They Really Work?"8

Calorie Restriction
Reduction in calorie intake by 20 to 40 percent (1200
calories for women versus 1400 calories for men per
day) over an extend period of time ranging from weeks
to months

Intermittent Calorie Restriction
Reduction in calorie intake by 50 to 70 percent (600–
1000 calories per day) for short periods of time, for
instance, once or twice per week

Fasting
Complete avoidance of calorie intake for anywhere from
one day to several weeks

Intermittent Fasting
Alternating a fasting day with a normal energy intake
day or fasting once or twice per week; typically, there
are no food restrictions on eating days, although eating
should be moderate rather than compensatory; there
are many versions of this plan, such as eating five days
a week and fasting for two

Daily Partial Fasting
Complete avoidance of calorie intake for 14–18 hours
daily; meals are resumed at the start of each day, but all
meals are eaten within a defined period of approximately
eight to ten hours9

Alternate-Day Dieting
Alternating a normal eating day with a calorie restriction
day of approximately 20 percent of typical calorie intake;
some writers call this alternate-day fasting

What Diets Do the Researchers Themselves Follow?
The author of the article mentioned above, "Running on
Empty," very helpfully queried caloric restriction and fasting
researchers as to the eating plans they practice themselves.
The following are some of the responses that he received.
Researchers give their rationales for various practices in the
body of the article.

Valter Longo, University of Southern California: Eats twice per day (skipping lunch) and practices a periodic fast for five days every six months

Mark Mattson, National Institute on Aging: Eats within a six-hour window every day and does trail running

Satchidananda Panda, Salk Institute: Eats within a 12-hour window every day and practices an extended water-only fast of five days once per year

Krista Varady, University of Illinois at Chicago: Practices alternate-day fasting one or two months per year, "usually after Christmas to shed the five pounds of holiday weight."

Back to Ketogenesis
Lean tissue loss with caloric restriction quite clearly is an issue, especially in anyone past middle age, at which point
regaining lean muscle tissue becomes much more difficult.
Fasting, of course, is ketogenic and some version of fasting
would appear to be more practical over the long term,
keeping mind, however, that those who are insulin resistant have difficulty in accessing fat stores for fuel and
thus will, again, sacrifice lean tissues for access to protein
in order to fuel the glucose requirements that are required
even with a ketogenic diet. A nice point about a ketogenic
diet is that there is greater freedom to consume essential
nutrients than is true of more extreme forms of fasting.

Recent research in animals suggests that, at least
in this model, a ketogenic diet extends longevity and
healthspan even when begun in adult animals.10 Similarly,
a ketogenic diet in this model promotes better memory in
this model.11 Interestingly, although rodents typically are
quite poor choices for testing high-fat diets due to their
inappropriate metabolism of high-fat diets compared
to humans, nevertheless, after animals made obese on
a high-fat diet had transitioned to a ketogenic diet, they
lost all excess body weight, exhibited improved glucose
tolerance and displayed increased energy expenditure.12
Likewise, there is improved antioxidant and free radical
protection under ketogenic diet conditions.13 Short- and
long-term ketogenic dieting improves select markers of
liver oxidative stress compared to standard rodent chow
feeding, although long-term ketogenic diet feeding may
negatively affect skeletal muscle mitochondrial physiology.
The picture is not entirely unmixed in the animal model
(there are contradictory outcomes regarding the impact on skeletal muscle mitochondria), yet overall conclusions
seem positive.14,15

Next month in these pages, it will be noted that even in
elite athletes of approximately 30 years of age, it can take
three months or more to adjust adequately to a ketogenic
diet. (See "Sports Supplements For Better Metabolic Flexibility
and Performance," May 2018 TotalHealth.) For those who
are older and not so physically elite, the transition might
well run six to twelve months, which is quite a long time for
a diet that is, frankly, difficult to follow except for Eskimos
and Tibetan nomads!

In light of these considerations, the question arises as
to whether there are alternatives to following a ketogenic
diet. Again, last month it was pointed out that many of the benefits of a ketogenic diet, including the ability to produce
and metabolize ketones, likely can be achieved by means
of a combination of diet and selected dietary supplements
to achieve metabolic fitness / metabolic flexibility. The other alternative considered was the consumption of ketone salts and/or esters. Although this route in animal research and in actual human trials has been shown thus far to be inferior for
both general and athletic purposes to a sustained ketogenic
diet,16 evidence is accumulating, at least in an animal model,
that consumed ketone bodies may mimic at least in part the lifespan-extending properties of caloric restriction. Indeed,
the argument is being made that calorie restriction extends
lifespan at least in part through increasing the levels of
ketone bodies.17

Conclusion
[B]illions of dollars have been spent on research into the
biological factors affecting body weight, but the near-universal
remedy remains virtually the same, to eat less
and move more. According to an alternative view, chronic
overeating represents a manifestation rather than the
primary cause of increasing adiposity. Attempts to lower
body weight without addressing the biological drivers of
weight gain, including the quality of the diet, will inevitably
fail for most individuals.

"Increasing adiposity: consequence or cause of
overeating?"18

The primary focus of this and related articles have been the concepts of metabolic fitness and metabolic flexibility. Human physiology and metabolism can adapt to a quite wide range of circumstances and can be "tweaked," likewise, with a broad number of approaches. Enhancing healthspan, even if perhaps not absolute lifespan, can be
achieved through caloric restriction, fasting and dietary
interventions involving properly balanced and selected
foods combined with nutrients / dietary supplements. Some
of these approaches are more easily sustainable under
modern conditions and habits than are others. Regardless
of the approach selected, basic physiology, not willpower,
needs to be the guiding principle. For most individuals, no dietary program will succeed in the long run that does
not address both biological drivers and the constraints of
life (personality, work, family, social obligations, etc.) as it
actually is lived.

For Sports and Health

Most readers who have heard of ketosis and ketogenesis
likely associate the concepts with dieting and the works of Dr.
Robert C. Atkins (Dr. Atkins’ Health Revolution, 1989; Dr. Atkins’
New Diet Revolution, 1992) that launched a bit of a movement
in the 1990s. Much less well known is the role of ketosis in
sports and the importance of being able to enter ketosis as an
aspect of metabolic flexibility, meaning the ability to rapidly and
easily shift between carbohydrates and fats as fuel substrates
to match, on the one hand, dietary sources of calories and, on
the other hand, particular physical demands for energy. In fact,
the health implications of metabolic flexibility are significant
and are related to the body’s degree of insulin sensitivity and
thereby to the components of the metabolic syndrome. The
latter condition often is defined as being based on insulin
resistance and associated with abdominal (central) obesity,
elevated blood pressure, elevated fasting plasma glucose, high
serum triglycerides and low high-density lipoprotein (HDL)
levels. This way of looking at matters makes ketogenesis and
metabolic flexibility major determinants of health. One does
not need to be diabetic or even pre-diabetic for these issues to
be important, a point that Harry Preuss, MD and various coauthors,
including myself, make in a recent article intended for
practicing physicians, “Importance of Fasting Blood Glucose in
Screening/Tracking Overall Health.”1,2

Not only athletes for reasons having to do with competition,
but also non-athletes for reasons of health likely would benefit
from some form of supplement protocol or other approach
that can achieve ketogenesis and maintain metabolic flexibility
without depending entirely on the diet. Indeed, achieving
ketosis via diet alone is hard to maintain over the long haul for
a variety of reasons. Eating mostly protein and fat may sound
like a treat at the beginning, but highly restricting all sources of
carbohydrates quickly leads to a boring diet and even limited
social interaction because few social events are built around
ketogenic snacks! It also means avoiding many or most sources
of phytonutrients, not eating adequate fiber for gut health and
bowel regularity, probably inadequately eliminating toxins via
the bile route in the stool, and even ramping up production
of the hormone cortisol.3 Extreme ketosis leads to unpleasant
breath (acetone breath) although this is not an issue with
moderate and healthy ketogenesis.

Background on Ketosis and Ketogenic Diets
There are only two primary sources of energy, carbohydrates
and fats. If needed for energy, protein can be broken down to
yield a carbohydrate component, not a fatty acid component.
Ketosis refers to the state in which the body meets its energy
requirements largely through the oxidation of ketone bodies.
These build up in the blood when glucose is not being used for
energy and even the brain can run on ketone bodies. Glycolysis
is the opposite number to ketosis in that it refers to the oxidation
of glucose, for which all carbohydrates ultimately are a source,
for energy. People sometimes associate ketosis with diabetes,
but ketosis is a nutritional process whereas in diabetes the body
either lacks sufficient insulin or cannot respond properly to
insulin and therefore builds up ketone bodies due to a failure of
metabolism while at the same time not properly harnessing fats
for fuel. There is plenty of evidence to the effect that ketogenic
diets can be healthful. Traditional Eskimo diets consisted almost
entirely of raw meat and blubber (fat) and yet the Eskimos did
not exhibit diabetes. Similarly, for certain neurologic conditions
children are raised from early life into their thirties or later
with completely normal physiologic and mental development
without eating any carbohydrates at all.

Athletes and some "paleodieters" speak of keto-adaptation,
which means simply moving the metabolism to preferentially
accessing stored fats as fuel sources rather than depending on
glucose. The body has quite limited stores of glycogen or "animal
starch" stored primarily in the liver in contrast to virtually
unlimited calories stored as fats. A quite standard assessment
is that there may be 400 grams of glycogen in the liver and
another 100 grams in the muscles. Glycogen is associated with
water on a 1:3 to 1:4 ratio. A major problem in achieving keto-adaptation
by diet alone is that most individuals who have been
raised on Western-style diets can take six months or more to
make the shift and this shift becomes ever more difficult as
we age. Studies examining the role of carbohydrates in the
metabolism with roughly 30 year old males in good physical
condition have revealed, for instance, that even transitioning
from a high glycemic index diet to a low glycemic index diet
while maintaining the same ratio of carbohydrate, fat and
protein can take more than four weeks. Shifting to fatty acid
metabolism for energy can be difficult.

High fat diets were employed at the turn of the century to
treat Type I diabetes, the form that begins in childhood with
the destruction of the insulin-producing cells of the pancreas.
Since the body can and will produce its own blood sugar from
protein in order to feed the brain, there is always some role for
insulin in the body regardless of the diet followed. Needless to
say, those with juvenile diabetes almost invariably died young
until the discovery of insulin.

In adult-onset or Type II diabetes, which typically begins
fairly late in life and with those already overweight, diet and
exercise often can completely control the problem. This and
other clues have led a number of researchers to suspect that
excess weight gain is related to insulin production either directly
or indirectly, as discussed briefly above. Dr. Robert C. Atkins was
one of the first to popularize the notion of dieting by bypassing
the insulin mechanism through eliminating most carbohydrates
from the diet while continuing to consume both proteins and
fats. Atkins' Diet is both high in protein and high in fat.

High protein, low fat/very low carbohydrate diets have
been common for some time, but not with the particular
justification that they bypass the insulin mechanism. Generally
the justifications have had to do with energy production, or
rather the lack of it on these diets. In the Stillman Diet, for
instance, it was argued that protein molecules are so large that
they use up extra energy as a food for the body. This diet calls for
the drinking of at least eight glasses of water a day, which truly
is necessary to remove the waste products of excess protein
consumption and from the oxidation of the body's own fats.

Very similar is the famous Scarsdale Diet, designed for use for
only two weeks at a time. Both strictly limit carbohydrates and,
somewhat less strictly, fats. Both do reduce weight in the short
term, but such large amounts of protein are hard on the body.
In contrast to these, the Dr. Atkins' Diet allows for unlimited
amounts of both proteins and fats, but for restricted amounts
of carbohydrates according to the theory that a faulty insulin
mechanism is the cause of excess weight. A more limited form
of this ketone-based diet popularized at about the same time as
the Atkins Diet is presented by Dr. Calvin Ezrin in The Endocrine
Control Diet (1990).

Athletes long have experimented with ketogenic diets. For
instance, during the 1990s a number of top bodybuilders in the
World Bodybuilding Federation adopted a diet similar to the one
Atkins uses (roughly 40 percent of calories from protein and
60 percent from fat) in order to cut body fat and build muscle.
These individuals were all undertaking extremely hard physical
labor, so the diet itself cannot be a source of fatigue, but must
in fact supply considerable energy.4 Nevertheless, even major
competition class athletes ultimately generally give up on
strict ketogenic diets. As admitted by Ben Greenfield, a serious
triathlete who was tested with regard to the ergogenic benefits
of a ketogenic diet, "after the study at University of Connecticut,
I personally quit messing around with ketosis and returned to
what I considered to be a more sane macronutrient intake of
50-60% fat, 20-30% protein, 10-30% carbohydrate."5

Ketogenesis with Supplements
Can ketogenesis be achieved using a more normal diet with
the help of supplements? The answer appears to be "yes."
Nevertheless, there are important considerations, among which
are the following:

The diet should not be high in simple sugars, fructose or refined carbohydrates. For non-athletes and those looking primarily to increase metabolic flexibility, the diet should resemble a modified Sears Diet, meaning approximately 20¨C 30 percent protein, 30¨C40 percent carbohydrate and 30¨C40 percent fat. For athletes and individuals who seriously want to initiate and maintain a fat-adapted diet, Ben Greenfield's suggestion is more in order: "50-60% fat, 20-30% protein, 10- 30% carbohydrate."

It is helpful to support fat metabolism directly such as through improved transport of fatty acids into the mitochondria for oxidation.

Insulin sensitivity must be improved and maintained and insulin levels kept low.

The release of fatty acids from fat cells likely is less important than is disinhibiting fatty acid metabolism. The first is accomplished with caffeine, yet often with a downside such as increased cortisol levels, hence alternatives to caffeine and other similar stimulants are needed.

Inclusion of substances that actively promote fatty acid oxidation is important to help kick-start the body's ability to metabolize fats.

Excessive gluconeogenesis by the liver (creation of glucose from glycogen in response to the release of glucagon) should be inhibited to promote fatty acid oxidation as the alternative.

With diets that are heavy in alcohol and fat, potential "reverse" effects must be prevented.

A small number of supplements, especially if taken together,
may fulfill the above requirements and actually have been tested
successfully in a pilot case. The subject in question was able to
consume a normal diet, indeed one that included quite a bit
of alcohol, by relying on only four supplements to remain in
moderate ketosis during much of the day: hydroxycitric acid,
wild bitter melon extract, sesame lignan extract and green
coffee bean extract. The sources of these supplements were
not generic and this should be kept in mind because different
production methods lead to different products with different
results. Published comparative trials, for example, with
hydroxycitric acid have shown this definitively.

Potassium-Magnesium Hydroxycitrate
The key component in supplement-support ketogenesis is
(-)¨Chydroxycitric acid (HCA). That some forms of properly
manufactured HCA can be used to encourage ketogenesis has
been known at least since 2000. In that year, Ishihara published
that HCA ingestion for 13 days increased fat oxidation and
improved endurance exercise time to fatigue by 43 percent
compared to a placebo in mice.6 Over the following few years,
three studies by Lim and others in trained athletes demonstrated
that ingestion of HCA enhances endurance performance via
increasing fat oxidation and sparing glycogen utilization during
moderate intensity exercise. In fact, in trained athletes HCA
ingestion for five days shifted fuel selection to fat oxidation
at both 60 percent and 80 percent VO2max during exercise.7
Lim further demonstrated a number of significant findings.
First, using mice as his model, he showed that chronic HCA
ingestion alters fuel selection rather than the simple release of
fat from stores as is true of lipolysis, i.e., mechanism for HCA
is not the same as with caffeine, capsaicin, etc. Second, Lim's
review data that showed that the combination of HCA plus
L-carnitine improves glycogen status in liver and various muscle
tissues versus placebo in exercised-trained rodents. Since the
publication of Lim's papers, this finding has been repeated
more than once with human athletes. Although L-carnitine
improves the effect, it is not necessary.8 Third, Lim in his
studies employed a pure synthesized trisodium hydroxycitrate
salt rather than commercial calcium or calcium-potassium
HCA salts, which did not yield his results. As is true of many
herbal products, the benefits of HCA are highly dependent
upon how the item is prepared. The acid must be stabilized by
the addition of high pH ions (basic or alkali), such as those of
potassium, magnesium or calcium. Using the wrong stabilizing
counter-ions results in little or no activity. In the case of the acid
derived from Garcinia cambogia and related sources, adding any
calcium at all reduces some desired benefits and blocks other
benefits entirely.9 This fact has been verified by more than one
comparative trial.

Another benefit of HCA that supports ketogenesis is its
impact on insulin sensitivity. At the 2005 Annual Meeting of the
American College of Nutrition for the first time it was reported
that the potassium-magnesium HCA salt in an animal model
gave the same blood glucose regulation as found in the control
arm of the test while almost literally cutting insulin levels in
half.10 The same study demonstrated that this salt dramatically
improved glucose clearance from the blood, lowered systolic
blood pressure and also lowered several key indicators of
inflammation, including C-reactive protein and tumor necrosis
factor-alpha (TNF-alpha). In contrast, the potassium-calcium
salt exerted no effect upon insulin and blood sugar regulation
and only very poorly influenced blood pressure.11 In the areas of
insulin metabolism, glucose regulation and blood pressure, the
proprietary potassium-magnesium salt was between five and
seven times as active as the potassium-calcium salt of the fruit
acid. A paper just published this year also indicates that HCA
may help to regulate thyroid hormones and promote muscle
protein synthesis.12

Wild Bitter Melon Extract and Sesame Lignan Extract
As indicated above, HCA appears to be extremely useful in
freeing the body's metabolism regulators to allow a shift
towards preferentially oxidizing fatty acids for energy. Increasing
insulin sensitivity and reducing insulin levels removes one of
the primary brakes on fatty acid metabolism. A complement to
these actions is direct activation of fatty acid oxidation. Both
wild bitter melon and sesame seed lignans help to do just this.
Bitter melon previously has been discussed in these pages
under the title, "Going WILD with Bitter Melon for Blood Sugar
Support."13 As noted in that article, it has been found that
extracts of bitter gourd activate cellular machinery to regulate
energy production (technically, AMP-activated protein kinase or
AMPK) and the way that fats are handled by the liver. These
components can account for as much as 7.1 g/ kg of the dried
wild material.

The sesamolin lignan found in sesame seeds (but not in
most extracts) likewise increases fat metabolism. As pointed
out in an important study, the "[e]ffects of sesamin and
sesamolin (sesame lignans) on hepatic fatty acid metabolism
were compared in rats. Sesamolin rather than sesamin can
account for the potent physiological effect of sesame seeds
in increasing hepatic fatty acid oxidation observed previously.
Differences in bioavailability may contribute to the divergent
effects of sesamin and sesamolin on hepatic fatty acid
oxidation. Sesamin compared to sesamolin was more effective
in reducing serum and liver lipid levels [with]sesamolin more
strongly increasing hepatic fatty acid oxidation." "Sesamolin
rather than sesamin can account for the potent physiological
effect of sesame seeds in increasing hepatic fatty acid oxidation
observed previously."14 "...gene expression of hepatic enzymes
involved in fatty acid oxidation [was] much stronger with
episesamin and sesamolin than with sesamin¡­[serum] half
lives of 4.7±0.2, 6.1±0.3 and 7.1±0.4 h for sesamin, espisesamin
and sesamolin, respectively...15

Green Coffee Bean Extract
After meals, up to 70 percent of the glucose from food is
stored in muscle and other lean tissues. However, moment-to-moment
regulation of blood glucose typically is handled by the
liver. It does this via two processes, both of which are highly
regulated. Gluconeogenesis generates glucose from certain noncarbohydrate
carbon substrates, including certain amino acids
and lipid components, such as triglycerides. Glycogenolysis is
the freeing of glucose from glycogen stores. In the liver, but
not the muscles, the hormone glucagon is involved. The liver
also uses the enzyme glucose-6-phosphatase. With aging and
as the metabolic syndrome develops, regulation of these two
processes becomes impaired. Dysregulation is a particularly
significant issue in diabetes.

Ketogenesis requires that the body preferentially use fatty
acids for fuel. This cannot happen if either gluconeogenesis or
glycogenolysis is not under proper control.

L-Carnitine and Astaxanthin
L-carnitine is a nutrient that, among other things, helps to
shuttle fatty acids into the mitochondria for oxidation. In the
discussion of HCA above it was noted that the combination
of HCA and L-carnitine greatly improves the replenishment
of glycogen stores after exercise. Unfortunately, tissue levels
of L-carnitine are highly regulated and difficult to elevate to
the extent necessary for ergogenic benefits in athletes. HCA
improves L-carnitine metabolism by increasing uptake.HCA is an
insulin memetic as well as an insulin sensitizer. HCA also shifts
the body towards metabolizing fats, which makes L-carnitine's
job easier. Another approach is to supplement with astaxanthin.
Astaxanthin (≥4 mg/d) has been shown to reduce lactic acid
accumulation during exercise, improve fatty acid oxidation and
maintain better blood glucose levels while improving endurance.
The mechanism may involve carnitine palmitoyltransferase I.18,19

Conclusion
Studies have demonstrated the importance of metabolic
flexibility for maintaining cardiovascular health and reducing the
risk of developing metabolic syndrome components. Likewise,
studies have shown that the related ability to enter ketosis as
needed for athletic purposes can render rich ergogenic rewards.
Nevertheless, enabling ketogenesis or keto-adaptation, however
desirable this might be, through dietary measures alone
under modern circumstances in Western countries is not only
inconvenient, but downright difficult. Fortunately, it is possible
to enable keto-adaptation through the use of appropriate
supplements. These include properly manufacture HCA salts,
wild bitter melon extract, sesame lignans and green coffee bean
extracts. L-carnitine and astaxanthin are two more supplements
that fit into this schema.

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